New role for brain receptor in control of body weight – research findings identify pathway for development of drugs to treat obesity

People who are resistant to the hormone leptin may become obese due to difficulties receiving bloodborne messages that tell their brain to reduce food intake or burn off excessive weight.

Research conducted at the University of Washington and Hoffmann-La Roche Inc. and published in the Nov. 27 issue of Nature identifies the role of the melanocortin-4 (MC4) receptor in rats as a mediator of the action of leptin, a hormone known to reduce food intake and body weight by acting on the central nervous system. If this finding holds true for humans, it may lead to the development of drugs for the treatment of obesity.

In their study, researchers found that rats who had their MC4 receptors chemically blocked were unaffected by treatment with leptin. Rats whose MC4 receptors were left unaltered consumed less food and lost weight when receiving the same amount of leptin.

“Several studies suggest that a person may become obese because their body is resistant to the effects of leptin,” explained Dr. Michael Schwartz, senior investigator and associate professor of medicine at the UW School of Medicine who also sees patients at Harborview Medical Center and Puget Sound VA Health Care System. “Our results suggest one approach – developing a drug treatment to activate the MC4 receptor – that might overcome this leptin resistance.”

Since leptin receptors are located on the same neurons in the brain which produce melanocortins, researchers suspected a connection between leptin-induced reductions in food intake and the melanocortin receptor. To test their premise, they pretreated a groups of rats with a drug that blocked activation of their MC4 receptor.

These rats, along with a control group of rats who were not pre-treated, then received doses of leptin. Researchers found that rats who received only leptin had significant decreases in food intake and that brain neurons in the hypothalamus that control appetite were activated. In contrast, rats who were pre-treated with the MC4 blocker showed no effects from leptin treatment. Activation of the melanocortin receptor system, therefore, appears to be required for leptin to act in the brain.

“Identifying a role for the MC4 receptor in mediating the effects of leptin in the brain may be an important step in advancing our understanding of how the brain controls food intake and body weight and, subsequently, will help us treat health problems such as obesity,” said lead author Dr. Randy Seeley, who conducted the research while on the UW faculty and who is now at the University of Cincinnati College of Medicine.

It was earlier this year that the MC4 receptor was first identified as a player in body weight regulation. Researchers note these additional study findings help support the idea that developing drugs to correct signaling pathways used by leptin may someday provide a mechanism for controlling body weight.

“The MC4 receptor is in a class of proteins that is particularly amenable to therapeutic intervention with small-molecule drugs,” notes co-author Dr. Keith Yagaloff, research leader in metabolic diseases at Hoffmann-La Roche. “A better understanding of this receptor may enable us to develop new therapeutic treatments for obesity.”

The research was funded by the National Institutes of Health and the Department of Veterans’ Affairs.